REVIEW Open Access

Role of angiotensin-converting enzyme 2(ACE2) in COVID-19Wentao Ni1†, Xiuwen Yang2†, Deqing Yang3†, Jing Bao1, Ran Li1, Yongjiu Xiao4, Chang Hou5, Haibin Wang6,Jie Liu7, Donghong Yang1, Yu Xu1*, Zhaolong Cao1* and Zhancheng Gao1*

Abstract

An outbreak of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that started inWuhan, China, at the end of 2019 has become a global pandemic. Both SARS-CoV-2 and SARS-CoV enter host cellsvia the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in various human organs. We havereviewed previously published studies on SARS and recent studies on SARS-CoV-2 infection, named coronavirusdisease 2019 (COVID-19) by the World Health Organization (WHO), confirming that many other organs besides thelungs are vulnerable to the virus. ACE2 catalyzes angiotensin II conversion to angiotensin-(1–7), and the ACE2/angiotensin-(1–7)/MAS axis counteracts the negative effects of the renin-angiotensin system (RAS), which playsimportant roles in maintaining the physiological and pathophysiological balance of the body. In addition to thedirect viral effects and inflammatory and immune factors associated with COVID-19 pathogenesis, ACE2downregulation and the imbalance between the RAS and ACE2/angiotensin-(1–7)/MAS after infection may alsocontribute to multiple organ injury in COVID-19. The SARS-CoV-2 spike glycoprotein, which binds to ACE2, is apotential target for developing specific drugs, antibodies, and vaccines. Restoring the balance between the RAS andACE2/angiotensin-(1–7)/MAS may help attenuate organ injuries.

Keywords: SARS-CoV-2, COVID-19, Angiotensin-converting enzyme 2, Multi-organ injury

BackgroundAt the end of 2019, an outbreak of a novel coronavirus(2019-nCoV) was reported in Wuhan, Hubei Province,China [1, 2]. The outbreak has become a global pan-demic. This virus seems to be much more contagiousthan severe acute respiratory syndrome (SARS) corona-virus (SARS-CoV) and Middle East Respiratory Syn-drome (MERS) coronavirus (MERS-CoV). By the end ofJune 8, 2020, there have been more than 7,000,000 con-firmed cases of coronavirus disease 2019 (COVID-19),with nearly 400,000 fatalities worldwide.

Full-length genome sequencing revealed that 2019-nCoV shares 79.5% sequence identity with SARS-CoV,and pairwise protein sequence analysis found that itbelonged to the class of SARS-related coronaviruses [3].Both 2019-nCoV and SARS-CoV enter host cell via thesame receptor, angiotensin-converting enzyme 2 (ACE2)[3]. Therefore, this virus was subsequently renamedSARS-CoV-2. Although the overall mortality rate ofCOVID-19 caused by SARS-CoV-2 is lower than that ofSARS and MERS, organ dysfunction, such as acute re-spiratory distress syndrome (ARDS), acute cardiac in-jury, acute hepatic injury, and acute kidney injury arequite common in severe cases. ACE2, a homolog ofangiotensin-converting enzyme (ACE), which isexpressed in a variety of human organs and tissues, hasextensive biological activities and can counteract thenegative role of the renin-angiotensin system (RAS) in

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* Correspondence: lizard_xy@163.com; dragonczl@263.net;zcgao@bjmu.edu.cn†Wentao Ni, Xiuwen Yang and Deqing Yang contributed equally to thiswork.1Department of Pulmonary and Critical Care Medicine, Peking UniversityPeople’s Hospital, Beijing, ChinaFull list of author information is available at the end of the article

Ni et al. Critical Care (2020) 24:422 https://doi.org/10.1186/s13054-020-03120-0

many diseases [4–6]. Considering that the spike proteinof SARS-CoV-2 interacts with ACE2, as does that ofSARS-CoV, COVID-19 may have a pathogenic mechan-ism similar to that of SARS. In this review, we will dis-cuss the role of ACE2 in COVID-19, and its potentialtherapeutic targets, aiming to provide more informationon the management of the epidemic.

RAS and ACE2The RAS is a complex network that plays an importantrole in maintaining blood pressure as well as electrolyteand fluid homeostasis, affecting the function of many or-gans, such as the heart, blood vessels, and kidneys [6].Angiotensin II (Ang-II), which is the most representativebioactive peptide in the RAS, widely participates in theprogression of cardiovascular diseases, such as hyperten-sion, myocardial infarction, and heart failure [7]. In theclassic RAS, renin cleaves the substrate angiotensinogento form the decapeptide angiotensin I (Ang-I), and then,ACE removes two amino acids at the carboxyl terminusof Ang-I to yield Ang-II (Fig. 1). To date, three Ang-IIreceptors have been identified, and the affinities of thesereceptors for Ang-II are similar, in the nanomolar range[7]. Among these receptors, angiotensin type 1 receptor(AT1R) binds to Ang-II, causing vasoconstriction, cellproliferation, inflammatory responses, blood coagulation,and extracellular matrix remodeling, whereas angioten-sin type 2 receptor (AT2R) counteracts the aforemen-tioned effects mediated by AT1R [8].In 2000, two independent research groups discovered

ACE2, a homolog of ACE, which can remove thecarboxy-terminal phenylalanine in Ang-II to form theheptapeptide angiotensin-(1–7) [4, 9]. In addition, underthe alternating effects of ACE2 and ACE, angiotensin-(1–7) can be formed without Ang-II (Fig. 1). In thismetabolic pathway, Ang-I is first hydrolyzed by ACE2 toform angiotensin-(1–9), and angiotensin-(1–9) is thenhydrolyzed by ACE to form angiotensin-(1–7). Ang-Ican also be directly converted to angiotensin-(1–7) byendopeptidases and oligopeptidases [6]. Because of thehigher affinity between ACE and Ang-I, the classicalpathway of Ang-II to angiotensin-(1–7) is more common[6]. Angiotensin-(1–7), as a ligand, binds to the G-protein-coupled receptor MAS, which produces the op-posite effect to that of Ang-II, and exerts a range offunctions in multiple organs/systems [5, 6]. In additionto catalyzing the production of angiotensin-(1–7), ACE2is involved in the uptake of amino acids in intestinal epi-thelial cells [10].

ACE2 mediates SARS-CoV-2 infectionEntry into host cells is the first step of viral infection. Aspike glycoprotein on the viral envelope of the corona-virus can bind to specific receptors on the membrane of

host cells. Previous studies have shown that ACE2 is aspecific functional receptor for SARS-CoV [11]. Zhouet al. showed that SARS-CoV-2 can enter ACE2-expressing cells, but not cells without ACE2 or cells ex-pressing other coronavirus receptors, such as aminopep-tidase N and dipeptidyl peptidase 4 (DPP4), confirmingthat ACE2 is the cell receptor for SARS-CoV-2 [3]. Fur-ther studies showed that the binding affinity of theSARS-CoV-2 spike glycoprotein to ACE2 is 10- to 20-fold higher than that of SARS-CoV to ACE2 [12]. Theprobable mechanism of SARS-CoV-2 entry into hostcells based on SARS-CoV studies is displayed in Fig. 2.Briefly, the receptor-binding domain of the spike glyco-protein binds to the tip of subdomain I of ACE2 [11–14]. Membrane fusion of the virus and the host cell isactivated after binding, and viral RNA is subsequentlyreleased into the cytoplasm, establishing infection. ForSARS-CoV infection, intact ACE2 or its transmembranedomain is internalized together with the virus [15]. Thecatalytically active site of ACE2 is not occluded by thespike glycoprotein, and the binding process is independ-ent of the peptidase activity of ACE2 [14]. Some trans-membrane proteinases (such as a disintegrin andmetallopeptidase domain 17 [ADAM17], transmembraneprotease serine 2 [TMPRSS2], and TNF-converting en-zyme) and proteins (such as vimentin and clathrin) maybe involved in the binding and membrane fusion pro-cesses [16–21]. For example, ADAM17 can cleave ACE2to cause ectodomain shedding, and TMPRSS2 can cleaveACE2 to promote viral uptake [16, 17].ACE2 is expressed in nearly all human organs in varying

degrees. In the respiratory system, the traditional immuno-histochemical method and recently introduced single-cellRNA-seq analysis revealed that ACE2 is mainly expressedon type II alveolar epithelial cells, but weakly expressed onthe surface of epithelial cells in the oral and nasal mucosaand nasopharynx, indicating that the lungs are the primarytarget of SARS-CoV-2 [22, 23]. Moreover, ACE2 is highlyexpressed on myocardial cells, proximal tubule cells of thekidney, and bladder urothelial cells, and is abundantlyexpressed on the enterocytes of the small intestine, espe-cially in the ileum [22–24]. The cell-free and macrophagephagocytosis-associated virus may spread from the lungs toother organs with high ACE2 expression through blood cir-culation (Fig. 2). For example, up to 67% of patients whodeveloped diarrhea during the course of SARS and quite anumber of patients with COVID-19 showed enteric symp-toms [25–27]. Active viral replication in enterocytes of thesmall intestine has been reported, and SARS-CoV-2 hasbeen successfully isolated from fecal specimens [28, 29].

ACE2 is associated with multi-organ injury in COVID-19Autopsies of SARS patients showed that SARS-CoV in-fection can cause injury to multiple organs, such as the

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heart, kidney, liver, skeletal muscle, central nervous sys-tem, and adrenal and thyroid glands, besides the lungs[30, 31]. Most critically ill patients with COVID-19 alsohad multiple organ damage, including acute lung injury,acute kidney injury, cardiac injury, liver dysfunction, andpneumothorax [32]. As with SARS and COVID-19,organ injury is also frequently observed in MERS, espe-cially the gastrointestinal tract and kidneys, while the in-cidence of acute cardiac injury is less common [33–36].Unlike SARS-CoV and SARS-CoV-2, MESR-CoV usesDPP4 as its entry receptor, which is mainly expressed onpneumocytes, multinucleated epithelial cells, and bron-chial submucosal gland cells of the lungs; epithelial cellsof the kidney and small intestine; and activated leuko-cytes [37–39]. DPP4 is not abundantly expressed on

myocardial cells [37–39]. Therefore, this indicates thatorgan involvement and injury is strongly associated withreceptor distribution in the body.According to the results of a series of studies on SARS,

the pathogenesis of COVID-19 should be complex. Thevirus-induced inflammatory responses, including the ex-cessive expression of cytokines and chemokines, exces-sive recruitment of inflammatory cells, insufficientinterferon response, and possible production of auto-antibodies are deemed to be vital factors in diseasepathogenesis [30]. Pro-inflammatory cytokines (PICs)and chemokines in plasma, such as interleukin (IL)-1,IL-6, IL-12, IL-8, monocyte chemoattractant protein-1(MCP-1), and interferon-gamma-inducible protein 10(IP-10), are significantly elevated in the plasma of

Fig. 1 The renin-angiotensin system (RAS) and ACE2/angiotensin-(1–7)/MAS axis. The protease renin converts angiotensinogen to Ang-I, which issubsequently converted to Ang-II by angiotensin-converting enzyme (ACE). Ang-II can bind to the angiotensin type 1 receptor (AT1R) to exertactions, such as vasoconstriction, hypertrophy, fibrosis, proliferation, inflammation, and oxidative stress. ACE2 can covert Ang-I and Ang-II toangiotensin-(1–7). Angiotensin-(1–7) binds to the MAS receptor to exert actions of vasodilation, vascular protection, anti-fibrosis, anti-proliferation,and anti-inflammation. Ang-II can also bind to the angiotensin type 2 receptor (AT2R) to counteract the aforementioned effects mediatedby AT1R

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patients with SARS [40, 41]. Significantly increasedplasma concentrations of these PICs were also found insevere patients with COVID-19 [1]. Autopsy studies ofSARS patients further found that PICs and MCP-1 werehighly expressed in SARS-CoV-infected ACE2+ cells,but not in tissues without infected ACE2+ cells, suggest-ing virus-induced local immune-mediated damage [42].In addition to acting as the receptor for SARS-CoV

and SARS-CoV-2, ACE2 hydrolyzes Ang-II to

angiotensin-(1–7), and the ACE2/angiotensin-(1–7)/MAS counteracts the negative effects of the RAS and ex-erts anti-inflammatory effects [6, 43]. Several studieshave shown that SARS-CoV infection can downregulateACE2 expression on cells, thereby disrupting the physio-logical balance between ACE/ACE2 and Ang-II/angio-tensin-(1–7) and subsequently causing severe organinjury [44–47]. Given that SARS-CoV-2 is a species ofSARS-related coronaviruses and uses ACE2 as its

Fig. 2 A model for the process of SARS-CoV-2 entering host cells in the lungs and attacking other organs. SARS-CoV-2 enters the lungs, wherethe spike glycoprotein of the virus binds to ACE2 on cells, allowing the virus enter the cells. Some transmembrane proteinases, such astransmembrane protease serine 2 (TMPRSS2) and a disintegrin metallopeptidase domain 17 (ADAM17) also participate in this process. Forexample, SARS-CoV-2 can use TMPRSS2 for spike protein priming in cell lines. The infected cells and inflammatory cells stimulated by viralantigens can produce pro-inflammatory cytokines (PICs) and chemokines to activate immunological reactions and inflammatory responses tocombat the viruses. Cell-free and macrophage-phagocytosed viruses in the blood can be transmitted to other organs and infect ACE2-expressingcells at local sites

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receptor, the downregulation of ACE2 expression maybe involved in multiple organ injury in COVID-19.Based on previous studies on SARS and recent studies

on SARS-CoV-2, the multiple organ injury in COVID-19(Fig. 3) and the possible role of ACE2 in organ injuryare described below.

Acute lung injuryAlthough the mortality rate in COVID-19 is lower thanthat in SARS and MERS, numerous patients have acutelung injury (ALI) after infection [26, 32]. Similar to thepathological features of SARS and MERS, severe diffusealveolar damage, such as extensive edema, hyaline mem-brane formation, inflammatory infiltrates, microthrombiformation, organization, and fibrosis, was also observedin COVID-19, but with more cellular fibromyxoid exu-dates in the alveoli and small airways [48, 49]. The roleof the RAS and ACE2 in ARDS/ALI has drawn great at-tention since the outbreak of SARS in 2003. Clinicalstudies have found that ACE insertion/deletion poly-morphism may be correlated with the severity of ARDS[50, 51]. High Ang-II levels in the lungs can increasevascular permeability and cause pulmonary edema [52,53]. Several studies have revealed the protective effectsof the ACE2/angiotensin-(1–7)/MAS axis in the lungs. Italleviates lung inflammation, fibrosis, and pulmonary ar-terial hypertension, as well as inhibiting cancer cellgrowth, tumor angiogenesis, and tumor metastasis [6,54–56]. In different animal models of ALI, ACE2-

knockout mice exhibited enhanced vascular permeabil-ity, increased lung edema, neutrophil accumulation, andmarked worsening of lung function compared with wild-type control mice [56]. Injection of recombinant humanACE2 protein or AT1R blockers into ACE2-knockoutmice could decrease the degree of ALI [56].SARS-CoV infection considerably reduces ACE2 ex-

pression in mouse lungs [46]. Further experimentsshowed that mere binding of recombinant SARS-CoVspike-Fc to human and mouse ACE2 could result in thedownregulation of cell-surface ACE2 expression [46].The spike-Fc protein worsened acid-induced ALI inwild-type mice, but did not affect the severity of lungfailure in ACE2-knockout mice, indicating that the effectof spike protein on ALI is ACE2-specific [46]. Studies oninfluenza also found that ACE2 was significantly down-regulated after H1N1 infection [57]. ACE2 deficiencysignificantly worsened the pathogenesis in infected mice,and inhibition of AT1 alleviated the severity of influenzaH7N9 virus-induced lung injury [58, 59]. Moreover,Ang-II levels were elevated in H5N1- and H7N9-infected patients, which was associated with the sever-ity of lung injury and predicted fatal outcomes inH7N9-infected patients [59, 60]. In patients withCOVID-19, plasma Ang-II levels were markedly ele-vated and linearly associated with viral load and lunginjury [61]. All these findings suggest that the RASand ACE2 downregulation contribute to the patho-genesis of lung injury in COVID-19.

Fig. 3 Main organs involved in COVID-19

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Acute cardiac injuryThe heart abundantly expresses ACE2, indicating that itis vulnerable to SARS-Cov-2 infection. Autopsies of pa-tients with SARS revealed that 35% of them (7 of 20)were positive for the SARS-CoV genome in cardiac tis-sue, and patients with SARS-CoV cardiac infections hada more aggressive illness and earlier mortality than thosewithout [47]. Edema of the myocardial stroma, inflam-matory cell infiltration, and atrophy of cardiac muscle fi-bers was observed in patients with SARS and myocardialdamage [30, 31, 62–64]. Cardiac injury is quite commonamong severely ill patients with COVID-19, and wefound that early acute myocardial injury was associatedwith a higher risk of mortality [65].The beneficial role of the ACE2/angiotensin-(1–7)/

MAS axis in the heart has been well demonstrated [6]. Itcan induce vasorelaxation of coronary vessels, inhibitoxidative stress, attenuate pathological cardiac remodel-ing, and improve postischemic heart function [66].ACE2 expression usually increases at the initial stage ofheart injury, but decreases as the disease progresses [7].ACE2 knockout in mice results in myocardial hyper-trophy and interstitial fibrosis and accelerates heart fail-ure [67, 68]. In addition, ACE2 knockout in miceaggravates cardiac dysfunction caused by diabetes [69].In both SARS-CoV-infected mice and humans, ACE2expression in myocardial cells is markedly downregu-lated in the heart [47]. According to recent studies [26,70] and our data [65], a substantial number of patientswith severe disease have hypertension as a comorbidity.Over-activation of the RAS may have already occurredin these individuals before infection. The significantdownregulation of ACE2 and upregulation of Ang-II inCOVID-19 results in RAS over-activation, and loss ofthe protective effects of angiotensin-(1–7) may aggravateand perpetuate cardiac injuries.

Digestive system injuryThe gastrointestinal tract, especially the intestine, is vul-nerable to SARS-CoV and SARS-CoV-2 infections.SARS-CoV particles have been detected in epithelialcells of the intestinal mucosa, but not in the esophagusand stomach [30, 42]. The main pathological finding inthe intestines of patients with SARS was the depletion ofmucosal lymphoid tissue [71]. Only mild focal inflamma-tion was detected in the gastrointestinal tract [71]. Thesefindings may explain why gastrointestinal manifestationsin COVID-19 are not severe and are transient.Many patients with COVID-19 show a slight to mod-

erate increase in serum levels of alanine aminotransfer-ase (ALT) and/or aspartate aminotransferase (AST)during the course of infection [26, 72]. Autopsies ofSARS patients revealed fatty degeneration, hepatocytenecrosis, and cellular infiltration in the liver [30].

However, SARS-CoV was not detected in the hepatic tis-sue of most patients autopsied [30]. Both immunohisto-chemistry and single-cell RNA-seq analyses showed thathepatocytes, Kupffer cells, and the endothelial lining ofthe sinusoids were negative for ACE2; only cholangio-cytes were positive for ACE2 [22, 23, 73]. Gamma-gluta-myl transpeptidase (GGT), which reflects cholangiocytedamage, was elevated in some COVID-19 patients [74].These findings indicate that most acute hepatic injurymay not be due to virus infection, but is highly likely dueto other causes, such as drug hepatotoxicity, hypoxia, andsystemic inflammation. Whether SARS-CoV-2 causesdamage to the bile ducts by binding with ACE2 on cho-langiocytes requires further investigation.

Acute kidney injuryACE2 is highly expressed in the kidney, especially in theapical membranes of proximal tubular epithelial cells,suggesting that the kidney is another target of SARS-CoV-2 [22, 23, 75]. Moreover, an imbalance betweenAng-II and angiotensin-(1–7) caused by ACE2 deficiencymay aggravate the vulnerability of the kidney to otherfactors causing acute kidney injury (AKI) [76]. SARS-CoV was detected in epithelial cells of the distal tubules,and viral sequences were identified in urinary samplesfrom some patients [77, 78]. SARS-CoV-2 has also beenisolated from urinary samples [79]. A retrospective ana-lysis of 536 SARS patients showed that 6.7% of patientsdeveloped acute renal impairment during the course ofthe disease [80]. A large cohort study from New Yorkshowed that the incidence of AKI among patients withCOVID-19 could reach 36.6% [81].

Other organ and tissue injuriesPancreasPancreatic cells highly express ACE2, indicating thatCOVID-19 may affect the pancreas [82]. It has been re-ported that up to 16% of patients with severe COVID-19have elevated serum amylase and lipase levels, with 7%displaying accompanying significant pancreatic changeson CT scans [83]. Clinical presentation of acute pancrea-titis has been reported in patients with COVID-19 [84].ACE2/angiotensin-(1–7) plays a protective role in dia-betes by improving pancreatic β cell survival, stimulatinginsulin secretion, and reducing insulin resistance [6].Studies have shown that, compared to patients withnon-SARS pneumonia, many more SARS patients whohad no previous diabetes and had not received steroidtreatment developed insulin-dependent acute diabetesduring hospitalization [85, 86]. Moreover, plasma glu-cose levels and diabetes are independent predictors ofmortality in patients with SARS [86]. Autopsies of someSARS patients found atrophy and amyloid degenerationin most pancreatic islets, suggesting the virus causes

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damage to the islets [64]. Therefore, COVID-19 mayalso influence pancreatic function, similar to SARS, andglucose levels should be closely monitored, especially inpatients with diabetes or glucocorticoid treatment.

Skeletal musclesMuscle weakness and elevated serum creatine kinase(CK) levels were observed in more than 30% of patientswith SARS [87]. Mildly to moderately elevated CK levelswere also observed in patients with COVID-19 on ad-mission [88]. Myofiber necrosis and atrophy were ob-served in skeletal muscle tissues, but no SARS-CoVparticles were detected by electron microscopy [30, 89].Recent studies revealed that the RAS plays an importantrole in the pathogenesis of various skeletal muscle disor-ders, and the ACE2/angiotensin-(1–7)/MAS axis exertsprotective effects against muscle atrophy [6]. Neverthe-less, whether SARS-CoV-2 attacks the muscles andwhether the downregulation of ACE2 is associated withmyopathy is unclear.

Central nervous systemACE2 is widely present in the brain, predominantly inneurons, and participates in the neural regulation ofbroad physiological functions, such as cardiovascularand metabolic activities, stress response, and neurogen-esis [6, 90, 91]. In a mouse model, SARS-CoV invadedthe brain through the olfactory bulb and then spreadtransneuronally to other areas [92]. Olfactory and gusta-tory dysfunctions have been reported in many patientswith COVID-19, suggesting the involvement of the ol-factory bulb in SARS-CoV-2 infection [93, 94]. SARS-CoV was isolated from human brain tissue specimens[31, 95]. Autopsies showed edema and focal degener-ation of neurons in the brains of patients with SARS [30,31]. Many patients (78/214) had neurologic manifesta-tions in COVID-19, and SARS-CoV-2 was detected inthe cerebrospinal fluid of a patient with encephalitis [96,97]. Considering that SARS-CoV-2 has a much higheraffinity for its receptor (ACE2) than SARS-CoV, theformer could be capable of infecting and damaging thecentral nervous system.

Blood vesselsACE2 is also expressed in the endothelial cells of smalland large blood vessels, and the vascular endotheliumcan produce angiotensin-(1–7) [6, 22]. The ACE2/angio-tensin-(1–7)/MAS axis induces vasodilatory, antiprolifer-ative, and antithrombotic effects in the vasculature [6].SARS RNA can be detected in the endothelia of thesmall veins in many tissues [98]. Plasma D-dimer levelsare significantly elevated in severely ill patients withCOVID-19 [1, 32, 72], and the occurrence of dissemi-nated intravascular coagulation (DIC) at the early stage

of the disease is not rare. Viral infection and inflamma-tory responses damage the integrity of the vascularendothelium, causing increased permeability, coagula-tion activation, and microcirculation disturbances, whichmay contribute to organ injury in COVID-19.

Potential targets and drugsAs ACE2 is the receptor for both SARS-CoV and SARS-CoV-2, and some transmembrane proteinases such asADAM17 and TMPRSS are involved in binding andmembrane fusion processes, these sites may be potentialtargets in the development of antiviral drugs forCOVID-19 treatment. For example, serum samples frompatients with convalescent SARS can neutralize spike-driven entry of SARS-CoV-2 into host cells, suggestingthat vaccines targeting the spike protein will be promis-ing [18]. Studies have found that SARS-CoV-specificmonoclonal antibodies and recombinant ACE2-Ig canpotently neutralize SARS-CoV-2, and a hexapeptide ofthe receptor-binding domain of the spike protein bindsto ACE2, thus blocking SARS-CoV entry [18, 99–101].The downregulation of ACE2 in organs after virus in-

fection disturbs the local balance between the RAS andACE2/angiotensin-(1–7)/MAS axis, which may be asso-ciated with organ injuries. Animal studies have foundthat ACE inhibitor (ACEI) therapy can increase plasmaangiotensin-(1–7) levels, decrease plasma Ang-II levels,and increase cardiac ACE2 expression, whereas angio-tensin II receptor blockers (ARBs) can increase theplasma levels of both Ang-II and angiotensin-(1–7) aswell as the cardiac expression and activity of ACE2[102]. Thus, the use of ACEIs/ARBs, renin inhibitors,and angiotensin-(1–7) analogs may attenuate organ in-juries by blocking the renin-angiotensin pathway and/orincreasing angiotensin-(1–7) levels [103]. Other animalstudies showed that ALI mediated by SARS-CoV spikeor the influenza virus in mice could be rescued by theuse of ARBs [46, 60, 104]. In a population-based study,the application of ACEIs and ARBs significantly reducedthe 30-day mortality rate of patients with pneumonia re-quiring hospitalization [105]. There are also concernsthat treatment with ACEIs/ARBs may facilitate infectionand increase the risk of developing severe and fatalCOVID-19 by increasing ACE2 expression levels in tar-get organs [106]. However, two large cohort studiesshowed that ACEIs/ARBs use was not associated withincreased SARS-CoV-2 infection, but was associatedwith a lower risk of all-cause mortality in hospitalizedpatients [107, 108]. Further studies are needed to testthe protective effects of ACEIs/ARBs in COVID-19.

ConclusionsThe RAS and ACE2/angiotensin-(1–7)/MAS axis play im-portant roles in various physiological and pathophysiological

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contexts. Both SARS-CoV-2 and SARS-CoV use ACE2 asthe receptor for entry into host cells. Because ACE2 is highlyexpressed in various organs and tissues, SARS-CoV-2 notonly invades the lungs but also attacks other organs withhigh ACE2 expression. The pathogenesis of COVID-19 ishighly complex, with multiple factors involved. In additionto the direct viral effects and inflammatory and immune fac-tors, the downregulation of ACE2 and imbalance betweenthe RAS and ACE2/angiotensin-(1–7)/MAS axis may alsocontribute to the multiple organ injuries in COVID-19. Thespike glycoprotein of SARS-CoV-2 is a potential target forthe development of specific drugs, antibodies, and vaccines.Restoring the balance between the RAS and ACE2/angio-tensin-(1–7)/MAS may help attenuate organ injuries inCOVID-19.

AbbreviationsCOVID-19: Coronavirus disease 2019; SARS: Severe acute respiratorysyndrome; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2;ACE2: Angiotensin-converting enzyme 2; RAS: Renin-angiotensin system;MERS: Middle East Respiratory Syndrome; Ang-II: Angiotensin II;AT1R: Angiotensin type 1 receptor; AT2R: Angiotensin type 2 receptor;ARDS: Acute respiratory distress syndrome; DPP4: Dipeptidyl peptidase 4;PICs: Pro-inflammatory cytokines; MCP-1: Monocyte chemoattractant protein-1; IP-10: Interferon-gamma-inducible protein-10; ALI: Acute lung injury;ALT: Alanine aminotransferase; AST: Aspartate aminotransferase;GGT: Gamma-glutamyl transpeptidase; AKI: Acute kidney injury; CK: Creatinekinase; DIC: Disseminated intravascular coagulation; ACEI: ACE inhibitor;ARB: Angiotensin II receptor blocker

AcknowledgementsWe would like to thank Editage (www.editage.cn) for English languageediting.

Authors’ contributionsWN, XY, DY, and YX searched the literature. WN, YX, and JL analyzed thedata. WN, YX, DY, JB, RL, CH, HW, and DY drafted the manuscript. WN andDY created the figures. WN, YX, ZC, and ZG revised the final manuscript. Theauthors read and approved the final manuscript.

FundingThis study was supported by the National Natural Science Foundation ofChina (81903672), Peking University People’s Hospital Research andDevelopment Funds (RDY2018-14), and Ministry of Science and Technologyof China (2017ZX10103004006). The funding bodies had no role in thedesign of the study; in collection, analysis, and interpretation of data; and inwriting the manuscript.

Availability of data and materialsAll data generated and/or analyzed during this study are included in thispublished article.

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsAll authors declare no competing interests.

Author details1Department of Pulmonary and Critical Care Medicine, Peking UniversityPeople’s Hospital, Beijing, China. 2Department of Pulmonary and Critical CareMedicine, The Central Hospital of Wuhan, Tongji Medical College, HuazhongUniversity of Science and Technology, Wuhan, China. 3Division of PulmonaryDiseases, State Key Laboratory of Biotherapy of China, and Department of

Respiratory and Critical Care Medicine, West China Hospital of SichuanUniversity, Chengdu, China. 4Department of Emergency, The 940th Hospitalof Joint Logistics Support Force of Chinese People’s Liberation Army,Lanzhou, China. 5Department of Cardiology, Peking University People’sHospital, Beijing, China. 6Department of Endocrinology, The First AffiliatedHospital of Zhengzhou University, Zhengzhou, China. 7Department ofVascular and Endovascular Surgery, Chinese PLA General Hospital, Beijing,China.

Received: 10 March 2020 Accepted: 29 June 2020

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